US8784833B2 - Prenatal enzyme replacement therapy for hypophosphatasia - Google Patents
Prenatal enzyme replacement therapy for hypophosphatasia Download PDFInfo
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- US8784833B2 US8784833B2 US13/007,772 US201113007772A US8784833B2 US 8784833 B2 US8784833 B2 US 8784833B2 US 201113007772 A US201113007772 A US 201113007772A US 8784833 B2 US8784833 B2 US 8784833B2
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- tnsalp
- fusion protein
- fetus
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- enzyme
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- 238000002641 enzyme replacement therapy Methods 0.000 title abstract description 11
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
- C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
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- C07K2319/00—Fusion polypeptide
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- C07K2319/003—
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Definitions
- ERTs enzyme replacement therapies
- Those diseases include Gaucher, Krabbe, Fabry and Pompe diseases, as well as various mucopolysaccharidoses (MPS) and hypophosphatasia (HPP).
- MPS mucopolysaccharidoses
- HPP hypophosphatasia
- HPP is an inherited metabolic disorder that features rickets or osteomalacia caused by deficiency of tissue-nonspecific alkaline phosphatase (TNSALP; EC 3.1.3.1).
- TNSALP is an ubiquitous, cytosol-insoluble plasma membrane-bound enzyme.
- the human enzyme contains 524 amino acid residues, and the sequence is available on the UniProtKB/Swiss-Prot data base under the designation “PPBT-Human P05186”.
- Hypophosphatasia is an inherited metabolic disorder of defective bone mineralization caused by deficiency of the TNSALP. Clinical severity is remarkably variable, ranging from death in utero to merely premature loss of dentition in adult life. Despite the presence of TNSALP in bone, kidney, liver, and adrenal tissue in healthy individuals, clinical manifestations in patients with hypophosphatasia are limited to defective skeletal mineralization that manifests as rickets in infants and children and osteomalacia in adults.
- Acidic amino acid (AAA) oligopeptides bind specifically to bone matrix, hydroxyapatite calcium site, and tagging a therapeutic agent, namely TNSALP, with AAA markedly enhances delivery of the agent to bone [Nishioka et al., (2006) Mol Genet Metab, 88 (3):244-255].
- ERT has been successively shown by a deca-Asp (D 10 )-tagged TNSALP (sALP-FcD 10 ) in a HPP murine model (similar to the infantile form in human patients) to lead to marked clinical and pathological improvement [Milian et al., (2008) J Bone Miner Res, 23 (6):777-787].
- the sALP-FcD 10 enzyme is now used in Phase I and II clinical trials for HPP patients, resulting in substantial reversal of bone hypomineralization [Whyte et al., Hypophosphatasia: Treatment of Life-Threatening Disease Using Bone-Targeted Human Recombinant Tissue Non-Specific Alkaline Phosphatase (2009) ACR/ARHP Scientific Meeting, found at acr.confex.com/acr/2009/webprogram/Paper12463.html.
- This sALP-FcD 10 enzyme also includes the Fc region of human IgG at the C-terminus of the enzyme for purification purposes.
- ⁇ -glucuronidase is a cytosol- and water-soluble, sialic acid-containing glycoprotein enzyme that catalyzes breakdown of complex carbohydrates. Maternal IgG is transported transplacentally by the neonatal Fc receptor, which recognizes the Fc domain of IgG and mediates transcytosis from maternal to fetal circulation.
- polypeptides that are linked to an immunoglobulin fraction-crystallizable domain are able to cross the placenta and to enter the circulation of the fetus.
- Fc-domain immunoglobulin fraction-crystallizable domain
- one aspect of the invention contemplates a fusion protein comprised of a polypeptide peptide-bonded to a Fc-domain.
- a preferred polypeptide has a therapeutic use, such as a metabolic enzyme.
- a more preferred polypeptide is a cytosol-soluble (water-soluble) portion of a membrane-bound enzyme.
- a most preferred polypeptide is a tissue-nonspecific alkaline phosphatase (TNSALP).
- compositions that comprise an effective amount of an above-described fusion protein dissolved or dispersed in a pharmaceutically acceptable carrier.
- a pharmaceutically acceptable carrier is typically an isotonic aqueous buffer.
- Yet another aspect of the invention contemplates transplacental enzyme replacement therapy (ERT) for deficiency of a polypeptide such a TNSALP by administering a before-described pharmaceutical composition to a pregnant animal whose fetus or embryo is in need of such therapy.
- An exemplary fusion protein of such a composition comprises a water-soluble TNSALP portion, e.g., C-terminus-truncated TNSALP peptide-bonded to an IgG1 antibody Fc portion.
- Administration may be by any route, preferably intravenous or intraperitoneal administration of the fusion protein.
- Inborn errors of metabolism comprise diseases, which include MPS (such as MPS VII) and hyphosphatasia.
- the fusion protein (also some times referred to herein as a chimeric polypeptide) has a therapeutic domain and a Fc-domain as described herein.
- FIG. 1 is a graphic representation of the results of transplacental transfer of TNSALP-Fc after intravenous infusion into pregnant mice.
- FIG. 2 is a schematic drawing showing TNSALP-hFc constructions in mammalian expression vector pCXN.
- FIG. 3 is a schematic drawing showing a top view of SDS-PAGE results for purified TNSALP and TNSALP-hFc.
- FIG. 4 is a series of graphs showing the pharmacokinetics of different administration of infusions by using TNSALP-hFc.
- a fusion protein containing the IgG Fc-domain which after infusion into the maternal circulation, mediates delivery of the fusion protein across the placenta into the circulation of the fetus or embryo.
- An embryo is often described in the human context as existing from conception to about the eighth week, whereas a fetus is often described as being from about nine weeks to birth.
- the present invention contemplates a fusion protein having an IgG1 Fc peptide portion peptide bonded to a water-soluble (cytosol-soluble) portion of a biologically active polypeptide that is normally membrane-bound such as tissue-nonspecific alkaline phosphatase (TNSALP) or HMG-CoA reductase.
- TNSALP tissue-nonspecific alkaline phosphatase
- HMG-CoA reductase HMG-CoA reductase
- the present invention also contemplates a composition containing an effective amount of the fusion protein dissolved or dispersed in a pharmaceutically acceptable carrier.
- a method of treating a deficiency of that biologically active polypeptide in a fetus or embryo contemplates administering the pharmaceutical composition to the pregnant animal such as a mouse or a human whose fetus or embryo is in need of the biologically active polypeptide so that the fusion protein crosses the placenta.
- a contemplated fusion protein is dissolved, dispersed or admixed in a composition that is pharmaceutically acceptable and compatible with the active ingredient as is well known.
- pharmaceutically acceptable or “physiologically tolerable” refer to molecular entities and compositions that typically do not produce an allergic or similar untoward reaction, and the like, when administered to a host mammal.
- Suitable carriers can take a wide variety of forms depending on the intended use and are, for example, aqueous solutions containing saline, phosphate buffered saline (PBS), dextrose, glycerol, ethanol, or the like and combinations thereof.
- a composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, mineral oils, which enhance the effectiveness of the composition.
- a preferred embodiment contains at least about 0.01 percent to about 99 percent of an isolated fusion polypeptide of this invention as an active ingredient, typically at a concentration of about 10 to 200 mg of fusion protein per milliliter (ml) of carrier.
- a contemplated composition is conventionally administered parenterally as an aqueous composition, by injection, for example, intraperitoneally, subcutaneously or intramuscularly.
- the administration is provided to a pregnant human patient or suitable animal host such as a chimpanzee, mouse, rat, horse, sheep, mouse, dog, goat, bovine, monkey, or the like whose fetus or embryo is in need of the biologically active polypeptide.
- a contemplated composition is thus typically provided as a unit dosage amount in dry form that can be readied for administration by addition and mixing of deionized or distilled or other sterile water.
- the amount of fusion protein utilized in each administration is referred to as an effective amount and can vary widely, depending inter alia, upon the fusion protein, the genus of the animal to which the a fusion protein is administered, and the severity of the disease state being treated.
- An effective amount of a fusion protein at least temporarily improves the disease state for which the fusion protein is administered.
- heterozygous pregnant mice were infused with 10 U/g body weight of TNSALP-hFc on embryonic days 17.5 and that administration was successful in raising the level of TNSALP circulating in the fetal mice to almost twice the amount of enzyme present in untreated mice.
- the amount selected as an effective amount of a fusion protein can be determined for a given animal host and disease by a skilled worker without undue experimentation.
- HPP hypophosphatasia
- a fusion protein comprising the C-terminal, hydrophobic, membrane-spanning portion of TNSALP was expressed as a fusion protein with the IgG1 CH 2 —CH 3 hFc portion (TNSALP-hFc). That fusion protein was compared with the untagged recombinant TNSALP for clearance from the maternal circulation and delivery to the fetus.
- TNSALP-hFc To determine whether TNSALP-hFc could be transferred across the placenta, ALP activity in plasma of HPP newborns born from HPP heterozygous females mated with HPP heterozygous males was examined. It was observed that TNSALP-hFc, infused into pregnant mice on embryonic day 17.5, was transported across the placenta, whereas untagged TNSALP was not delivered to the fetus. These results are shown in FIG. 1 .
- the C-terminus-anchorless TNSALP enzyme was produced and the secreted form tagged with CH 2 —CH 3 hFc portion to form a fusion protein that was expressed using Chinese Hamster Ovarian (CHO) cell line and showed transplacental activity in fetus on hypophosphatasia mice with ERT.
- the present invention indicated that the enzyme with IgG1 CH 2 —CH 3 hFc portion is effective as a therapeutic agent transplacentally.
- This method is applicable to other proteins whose deficiency leads to the other human disorders with deficiency of an enzyme such as fetal hypolipidemia using the C-terminal membrane anchor truncated HMG-CoA reductase. See, U.S. Pat. No. 5,460,949 for a useful sequence.
- TNSALP and TNSALP-hFc were purified by the following two-step column procedure.
- Tris buffer was 25 mM Tris-HCl, pH 8.0, containing 0.1 mM magnesium chloride and 0.01 mM zinc chloride. Unless stated otherwise, all steps were performed at 4° C. The following procedure was followed:
- Step 1 The medium-containing enzyme was filtered through a 0.2 ⁇ m filter and then dialyzed against Tris buffer using Amicon stirred-cell ultrafiltration unit with Millipore ultrafiltration membrane YM-30.
- Step 2 The dialyzed medium was applied to a column of DEAE-Sepharose equilibrated with Tris buffer. The column was first washed with Tris buffer and then the enzyme was eluted with 0 to 0.4 M NaCl in a linear gradient.
- Step 3 The active eluted fractions were pooled and dialyzed against Tris buffer containing 0.1 M NaCl by using Centricon centrifugal filter device with Millipore ultrafiltration YM-10 filter. The dialyzed fractions were then concentrated for Step 4.
- Step 4 The concentrated enzyme was applied to a column of Sephacryl S-400-HR equilibrated with Tris buffer containing 0.1 M NaCl. The enzyme was eluted with Tris buffer containing 0.1 M NaCl.
- Step 5 The active eluted fractions were pooled and dialyzed against Tris buffer containing 0.1 M NaCl by using Centricon centrifugal filter device with Millipore ultrafiltration YM-10 filter. The dialyzed fractions were then concentrated and stored at ⁇ 80° C. until use.
- TNSALP and TNSALP-hFc activity were measured using the 250 ⁇ l of 10 mM p-nitrophenyl phosphate (pNPP) as substrate in 1 M diethanolamine, pH 9.8, containing 1 mM magnesium chloride, 0.02 mM zinc chloride, and incubated at 37° C.
- the time-dependent increase in absorbance at 405 nm (reflecting p-nitrophenolate production) was measured on a plate spectrophotometer.
- One unit of activity was defined as the quantity of enzyme that catalyzed the hydrolysis of 1 ⁇ mol substrate in 1 minute.
- Table 1 below provides the data analyses of the pharmacokinetics.
- TNSALP-hFc enzyme by intravenously (i.v), subcutaneously (s.c), and intraperitoneally (i.p) methods, and those administration dose concentration was fixed by 10 U/g body weight ( FIG. 4 ).
- the blood samples were collected to measure the level of TNSALP-hFc activity respective time course (0-48 hours).
- the peak concentration (Cmax) and concentration peak time (Tmax) were measured by original data.
- the area under the curve (AUC) was obtained with use of the lin-lin trapezoidal rule.
- the terminal elimination rate constant (ke) was calculated by log-linear regression of the final data points.
- the apparent elimination half-life time (T1 ⁇ 2) was calculated as follows: 0.693/ke.
- the mean residence time (MRT) was calculated to divide the area under the first moment curve by the AUC.
- the total clearance (CL) was calculated to divide the dose concentration by the AUC.
- the steady-state distribution volume (Vd) was calculated to divide the CL by the MRT.
- the bioavailability was calculated to divide the AUC of each administration method by the AUC of intravenous method. Those parameters were followed by actual TNSALP-hFc activity of each time point. The data for the parameters are found in Table 1 hereinbelow and are represented graphically in FIG. 4 .
- nucleotide base sequence is found in SEQ ID NO:1 and the derived amino acid residue sequence is provided in SEQ ID NO:2.
- Another aspect of the invention provides a composition comprising a nucleotide sequence as set forth in SEQ ID NO:1.
- the invention provides for a method for treating a metabolic disorder, such as HPP, in a fetus or embryo were a protein having a sequence as set forth in SEQ ID NO:2 is administered to a pregnant mother.
- the fusion protein comprises a Fc fragment of IgG1 and a soluable TNSALP.
- the protein crosses the placenta of the mother and enters the fetal blood stream.
- the protein is taken up into fetal tissue such that the TNSALP restores normal metabolic activity in the fetus.
- An isolated polypeptide of this invention can be formulated into a composition as a neutral or salt form.
- Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein or antigen) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be prepared from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine, and the like.
- a composition of this invention can be administered in a manner compatible with the formulation for the composition, and in such an amount as is effective to induce an antibody-producing immune response.
- the quantity of composition to be administered to achieve a desired result depends on the judgment of the practitioner and is peculiar to each individual host mammal, but are well known for laboratory hosts such as mice, rats, rabbits, goats and the like.
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Abstract
Description
TABLE 1 |
Pharmacokinetics |
Mice Age |
1 month-old |
Enzyme TNSALP-hFc |
injection manner | i.v | s.c | i.p |
Dose (U/g) | 10 | 10 | 10 |
T½ (hr) | 29.9 | 54.1 | 33.9 |
Tmax (hr) | 0.5 | 24 | 1 |
Cmax (U/mL) | 50.9 | 29.8 | 67 |
AUC (U/mL * hr) | 139.4 | 1172.3 | 1866.9 |
Bioavailability (%) | 100 | 840.7 | 1338.9 |
MRT (mean residence time) (hr) | 11.8 | 16.7 | 14.5 |
Vd (mL/g) | 0.848 | 0.143 | 0.078 |
CL (mL/(hr * g)) | 0.0717 | 0.0085 | 0.0054 |
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US11338020B2 (en) | 2018-01-09 | 2022-05-24 | Synthetic Biologics, Inc. | Alkaline phosphatase agents for treatment of neurodevelopmental disorders |
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